Cyclophosphamide vs. Chlorambucil in Metronomic Chemotherapy

Metronomic chemotherapy is a hot topic among Tripawds members who are fighting cancer. As more veterinary oncologists experience positive results with patients utilizing metronomic protocols, everyone is hungry for knowledge about this exciting option to stabilize and keep cancer in remission.

What is Metronomic Chemotherapy?

Unlike conventional chemotherapy, which calls for high doses of chemotherapy drugs given at separate intervals throughout the course of several weeks, metronomic chemotherapy patients are given much lower, continuous doses of an anti-cancer (“antineoplastic” or “cytotoxic”) drug on a daily basis. Metronomics works by preventing existing tumor cells from growing, by cutting off their blood supply.

Traditionally, veterinary oncologists have prescribed the drug Cyclophosphamide (brand name: Cytoxan) as the chemotherapy agent for metronomics.

However, some oncologists are incorporating other anti-cancer drugs such as Chlorambucil (brand name: Leukeran) and Melphalan (brand name: Alkeran) into their metronomic protocols, for patients who are experiencing cyclophosphamide’s side effects such as hemorrhagic cystitis (irritation of the urinary tract).

Chlorambucil and Melphalan in Metronomics

Tripawds members Sassy, Jill the Cat and Jackson have recently switched to chlorambucil for their own metronomic protocols. As a result, we were inspired to learn more about chlorambucil and melphalan by contacting world-renowned metronomic chemotherapy expert Dr. Barbara Biller, Veterinarian and Associate Professor of Oncology at Colorado State University Animal Cancer Center.

In a recent email interview, Dr. Biller was kind enough to share her knowledge about using chlorambucil and melphalan in metronomic chemotherapy protocols. Here’s what she had to say:

How long has Leukeran been used for metronomics? Why don’t more oncologists suggest Chlorambucil since we’ve heard it has fewer side effects (i.e. cystitis) than Cytoxan?

There is very little known about metronomic (anti-angiogenic) chemotherapy using Chlorambucil (same thing as Leukeran). There are no studies in any species (humans, mice, dogs, cats, etc) about its potential to slow or prevent tumor angiogenesis which is what metronomic chemotherapy is supposed to do. There are a lot of studies about Cytoxan that shows it is anti-angiogenic when used in a metronomic fashion. There is are only 2 published studies about using Leukeran in dogs with cancer (one published in 2012 and one in 2013).

In these papers they looked at the response of tumors to a “metronomic dose” of Leukeran but did not determine if the drug works in this fashion or if the dose was metronomic. No one knows what the metronomic dose of Leukeran would be in any species so you can’t even really guess.

What are the pros and cons of Chlorambucil (Leukeran) versus Cyclophosphamide (Cytoxan)?

Leukeran is very much more expensive than Cytoxan and we don’t know if it works in a metronomic fashion. It has side effects -biggest problem is bone marrow suppression when used for more than a month or two. For Cytoxan we have some idea of what the metronomic dose is in dogs (no clue in cats) and we have scientific data to tell us that it does work to slow tumor angiogenesis and help the immune system fight cancer – this data comes from studies in mice, humans and dogs. Yes

Cytoxan can cause cystitis (about 20% risk) but it is way less expensive and causes less problems with bone marrow suppression than Leukeran.

What is Leukeran’s cellular effect on the cancer, both as a preventive for future tumor growth and to help stabilize existing mets?

Leukeran is a chemotherapy drug that can kill tumor cells directly when used at standard cytotoxic doses. We don’t know if it works in a metronomic fashion.

Are there any studies documenting its efficacy?

Just two dog studies published as mentioned above looking at the tumor response to daily Leukeran at 4mg/m2. The overall response rate for these studies was less than 15% but some dogs had stable disease for a few months.

Why is there a big dosage difference for Leukeran versus Cytoxan? For example, a 130 pound rottie was prescribed 22 mg of Cytoxin but only 6mg of Leukeran. Since the dosage is lower, does that mean it’s a more powerful drug?

No, this is just the way the drug is made, nothing to do with potency.

We know of one oncolgoist using Alkeran for metronomics. Is this drug like Leukeran? How is different/alike?

Alkeran is in the same class of drugs as Leukeran and Cytoxan (all alkylating agents). It’s like comparing apples and oranges and bananas. No data for Alkeran as a metronomic agent exists that I am aware of.

What is your preferred drug for metronomics? Or does that depend on the animal and the client’s budget?

Obviously Cytoxan because there is human and dog data to tell us that it is anti-angiogenic when used in a metronomic fashion. Even with Cytoxan we are still guessing in terms of tumor types, drug schedules, monitoring response, etc. but for the others there is really no data to justify their use. There are some studies just starting now with Leukeran so I’d imagine in a year or two we will know more about this drug and whether it has any metronomic properties.

We’d like to thank Dr. Biller for her time in helping us discover as much as possible about fighting cancer in our dogs and cats with metronomic chemotherapy. If you have a metronomic chemotherapy experience you’d like to share, please contact us today.

Recommended Reading

Tripawds Downloads Blog: Metronomic Chemotherapy News Podcast on Tripawd Talk Radio
Tripawds Discussion Forums: Metronomic Chemotherapy for Canine Osteosarcoma
Tripawds Discussion Forums: Jackson’s Urinary Cystitis
Tripawds Discussion Forums: Jill’s Metronomic Chemotherapy Experience

Please remember, we are not veterinarians and this article is not meant to replace veterinary care for your Tripawd. Always discuss your Tripawds’s specific condition with your oncologist before making any changes to your daily routines. Thanks!